The present invention provides a pharmaceutical composition containing Tetrahydro Cannabinol (THC), having analgesic, anti-emetic, anti-nausea and anti-glaucoma properties, which is easily absorbed into the body at a steady rate to achieve a desired concentration in the bloodstream. Further, methods are provided for forming the pharmaceutical composition into a gel or powder, and for applying the gel or powder to form of the pharmaceutical composition to a transdermal patch for application to a human or animal body.
Marijuana contains many compounds. The major active compound thereof has been identified as DELTA.Sup Tetrahydrocannabinol (THC), also known as DELTA 9-THC depending on the carbon numbering convention used. THC and other compounds in marijuana have, in addition to promoting psychoactivity, been reported to provide beneficial effects. There are many research publications reporting beneficial activities like analgesic, antiemetic, and antiglaucoma effects. It has also been found that a major contributor of these beneficial effects is THC.
THC is effective as an analgesic, antiemetic, in anorexia, and for treating the nausea and frequent vomiting caused by cancer chemotherapy. THC is currently being given only orally, but is occasionally ineffective when taken in this form. For example, a metaanalysis study revealed a poor or only partial response to THC in approximately 65% of 750 courses of oral therapy. Thus, high single doses are administered which may cause undesirable side effects such as sedation, confusion and anxiety. Such poor response to oral administration of THC may be due to the limited aqueous solubility of THC, its extensive first pass metabolism following oral administration, and the resulting low absolute bioavailability of THC (13% on an average).
In addition, it has been noted that fasting or food deprivation could decrease the rate of absorption of THC from sesame oil capsules currently available in the market. Previous studies have also reported that another limitation of orally administered THC is the large intersubject variability in absorption. For this reason it would be important to titrate the THC dose on an individual basis, since the drug has biphasic activity and a relatively narrow therapeutic index.
In an attempt to overcome such problems, transdermal patches have been proposed. For example, U.S. Pat. No. 6,113,940 discloses a xe2x80x9cpatch-likexe2x80x9d device, utilizing a backing layer with a reservoir for holding the cannabis. The cannabis preparation uses, as a carrier for the cannabis preparation, a polymer matrix (the cannabis being suspended within the polymer matrix.). This method uses a xe2x80x9cporous membrane, nonporous membrane, polymer film, polymer membrane.xe2x80x9d
As with the above delivery system, U.S. Pat. No. 6,132,762 consists of a xe2x80x9cpatch-likexe2x80x9d device containing a reservoir for holding a cannabis preparation. The reservoir therein holds a gel comprised of at least one member selected from the group consisting of guar gum, gelatin, carboxymethylcellulose, carrageenan and agar. Additional steps of heating and cooling the formulation are needed prior to its intended use of treating joint pain, muscle pain or arthritis. Further, the backing layer contemplates an adhesive for holding the backing layer on/against the skin of the user.
U.S. Pat. No. 6,328,992 addresses the problems discussed above by providing a cannabis preparation comprising a 1-50 weight percent cannabis, 1-15 weight percent skin enhancer and about 10-90 weight percent of a transdermal carrier that may, as with a number of the previously discussed patents, be placed on a patch, strip, bandage and covering for holding the preparation. The transdermal carrier may be comprised of natural rubber, viscoelastic semi-solid materials, hydrogels, thermoplastic polymers, elastomer, amnd thermoelastomers, as well as an oil selected mineral oils, vegetable oils, fish oils, animal oils, carbon tetrachloride, ethanolic solutions of resins and pyrahexyl mixtures. To achieve its desired purpose, the preparation, an aggregation of numerous cannabinols, is delivered at a rate of 17 ug/sq.cm./hour.
However, all of the above encounter various problems. In view of the problems encountered with oral administration of THC as discussed above, the present inventors performed extensive research in order to provide a safe, reliable and effective method of delivery of THC, and a composition to use in performing same. It was then unexpectedly discovered by the present inventors that the problems associated with oral administration of THC can be minimized by the administration of the pharmaceutical composition containing THC of the present invention, which provides sustained low doses of THC via a transdermal route. Further, it was found that forming the composition of the present invention into a gel formulation as disclosed herein, which is applied on the skin of the patient""s body, or by applying as a transdermal patch on the skin of the patient""s body, provides a very effective method of delivery of the active ingredient.
Specifically, a pharmaceutical composition is provided consisting of between 1-10% by weight of THC (including specifically delta-9 THC, and more generally, all cannabinols), 1-5% of enhancer, 0.5%-5% neutralizer and a carrier containing approximately 70% alcohol and 25% water, rather than the enumerated oils and elastomer materials disclosed in U.S. Pat. No. 6,328,992. Further, there is no need in the present invention to use polyisoprene elastomers and styrene-butadiene block co-polymers in the formulation. Rather, the present invention uses polymers of acrylic acid and polymers of acrylic acid crosslinked with allylpetnearythritol. This composition of the present invention is able to overcome the difficulties discussed above, and achieve the objects of the present invention, by providing a pharmaceutical composition containing a relatively low dose of delta-9 THC (but with the potential to use other cannibinols) with a delivery rate of only 10.8 ug/sq.cm./hour (to treat nausea and loss of appetite).
In view of the deficiencies associated with the oral methods of delivery of THC discussed above, as well as conventional transdermal patches, it is an object of the present invention to provide a pharmaceutical composition containing tetrahydrocannabinol, which can be applied via a transdermal/transcutaneous route to a patient.
In view of the above, in a first embodiment of the present invention, a pharmaceutical composition is provided comprising tetrahydrocannabinol (THC), ethanol, polyethylene glycol, polymethacrylic acid, isopropyl myristate, carbopol, triethanolamine, propylene glycol, and acetone.
In a second embodiment of the present invention according to the first embodiment above, a pharmaceutical composition is provided, comprising:
from greater than 0 to 5 wt % tetrahydrocannabinol (THC);
40-70 wt % ethanol;
3-10 wt % polyethylene glycol;
5-20 wt % polymethacrylic acid;
from greater than 0 to 5 wt % isopropyl myristate;
from greater than 0 to 10 wt % carbopol;
from greater than 0 to 5 wt % triethanolamine;
5-50 wt % propylene glycol; and
20-50 wt % acetone.
In a third embodiment of the present invention according to the first embodiment above, a pharmaceutical composition is provided, comprising:
about 0.5 to about 2 wt % tetrahydrocannabinol (THC);
about 65 wt % ethanol;
about 4.7 to about 5.7 wt % polyethylene glycol;
about 10 to about 14 wt % polymethacrylic acid;
about 0.5 to about 1 wt % isopropyl myristate;
from greater than 0 to about 5 wt % carbopol;
from about 0.47 to about 1 wt % triethanolamine;
from about 10 to about 30 wt % propylene glycol;
about 35 wt % acetone, and
water.
In a fourth embodiment of the present invention, a pharmaceutical composition is provided according to the first embodiment described above, further containing a permeation enhancer.
In a fifth embodiment of the present invention, a pharmaceutical composition is provided according to the fourth embodiment above, wherein the pharmaceutical composition contains 2-10 wt % permeation enhancer.
In a sixth embodiment of the present invention, a pharmaceutical composition is provided according to the fourth embodiment above, wherein the pharmaceutical composition contains about 5 wt % permeation enhancer.
In a seventh embodiment of the present invention, a pharmaceutical composition is provided according to the fourth embodiment above, wherein the permeation enhancer is caproic acid.
In an eighth embodiment of the present invention, a pharmaceutical composition is provided according to the fourth embodiment above, wherein the permeation enhancer is caprylic acid.
In a ninth embodiment of the present invention, a pharmaceutical composition is provided according to the fourth embodiment above, wherein the permeation enhancer is lauric acid.
In a tenth embodiment of the present invention, a pharmaceutical composition is provided according to the fourth embodiment above, wherein the permeation enhancer is oleic acid.
In an eleventh embodiment of the present invention, a pharmaceutical composition is provided according to the fourth embodiment above, wherein the permeation enhancer is TWEEN 80.
In a twelfth embodiment of the present invention, a pharmaceutical composition is provided according to the fourth embodiment above, wherein the permeation enhancer is selected from the group consisting of caproic acid, caprylic acid, lauric acid, oleic acid and TWEEN 80.
In a thirteenth embodiment of the present invention, a method of manufacturing the composition of the first through tenth embodiments described above is provided, the method comprising:
(a) combining/mixing ethanol, polyethylene glycol, polymethacrylic acid, tetrahydrocannabinol (THC), isopropyl myristate, carbopol, triethanolamine, optionally a permeation enhancer, propylene glycol, acetone, and water to form a complex;
(b) drying the complex using heat to form a dried complex;
(c) milling the dried complex to form a powder; and
(d) adding a lower alcohol to the powder to form a gel.
In a fourteenth embodiment of the present invention according to the thirteenth embodiment above, a method of manufacturing the composition of the first through eighth embodiments described above is provided, the method further comprising:
mixing the elements in step (a) at a temperature of from 25-70xc2x0 C.
In a fifteenth embodiment according to the thirteenth embodiment above, a method of manufacturing the composition of the first through twelfth embodiments described above is provided, the method further comprising:
drying the complex is step (b) at a temperature of from 25-70xc2x0 C.
In an sixteenth embodiment according to the thirteenth embodiment above, a method of manufacturing the composition of the first through twelfth embodiments described above is provided, the method further comprising:
performing the drying step (b) for 4-12 hours.
In an seventeenth embodiment according to the thirteenth embodiment above, a method of manufacturing the composition of the first through twelfth embodiments described above is provided, the method further comprising:
mixing the components in step (a) for 1-4 hours.
In an eighteenth embodiment according to the thirteenth embodiment above, a method of manufacturing the composition of the first through twelfth embodiments described above is provided, the method further comprising:
mixing the components in step (a) at a stirring rate of 60-300 RPM""s.
In a nineteenth embodiment of the present invention, a method of manufacturing the composition of the first through twelfth embodiments described above is provided, the method further comprising:
(a) combining/mixing ethanol, polyethylene glycol, polymethacrylic acid, tetrahydrocannabinol (THC), isopropyl myristate, carbopol, triethanolamine, a permeation enhancer, propylene glycol, acetone, and water at a temperature of from 25-70xc2x0 C., and stirring same at a rate of 60-300 RPM""s for 1-4 hours to form a complex;
(b) drying the complex at a temperature of from 25-70xc2x0 C. for 1-4 hours to form a dried complex;
(c) milling the dried complex to form a powder; and
(d) adding a lower alcohol to the powder to form a gel.
In a nineteenth embodiment of the present invention, a method of manufacturing the composition of the first through twelfth embodiments described above is provided, the method further comprising:
(a) combining/mixing ethanol, polyethylene glycol, polymethacrylic acid, tetrahydrocannabinol (THC), isopropyl myristate, carbopol, triethanolamine, a permeation enhancer, propylene glycol, acetone, and water at a temperature of from 40-60xc2x0 C., and stirring same at a rate of 60-300 RPM""s for 1-4 hours to form a complex;
(b) drying the complex at a temperature of from 40-60xc2x0 C. for 1-4 hours to form a dried complex;
(c) milling the dried complex to form a powder; and
(d) adding a lower alcohol to the powder to form a gel.
In a twentieth embodiment of the present invention, a method of manufacturing the pharmaceutical composition of the first through twelfth embodiment described above is provided comprising:
mixing carbopol and polymethacrylic acid in ethanol to form a first solution;
mixing polyethylene glycol or polypropylene glycol in ethanol to form a second solution;
mixing the first and second solutions to form a third solution;
mixing isopropyl myristate and triethanolamine into the third solution as necessary;
mixing tetrahydrocannabinol with ethanol to form a fourth solution;
mixing the third and fourth solutions to form a pharmaceutical composition according to the present invention.
In an twenty first embodiment of the present invention, a transdermal/transcutaneous delivery system for THC is provided comprising the pharmaceutical composition of the first through twelfth embodiments described above.
A twenty second embodiment of the present invention is provided according to the twenty first embodiment described above, wherein the transdermal/transcutaneous delivery system further comprises a gel, patch or cloth for application onto the skin of a patient.
In twenty third embodiment of the present invention, a method for manufacturing the gel, patch or cloth of the twenty second embodiment described above is provided comprising addition of the gel formed in the second embodiment to a patch or cloth suitable for application in human or animal skin.
In a twenty fourth embodiment of the present invention, a method of manufacturing a transdermal patch or cloth containing a pharmaceutical composition containing THC is provided comprising addition of carbopol/poly methacrylic acid in Ethanol to Poly ethylene glycol or Propylene glycol in ethanol to form a first solution, mixing the first solution with a solution containing isopropyl myristate or triethanolamine to form a second solution, mixing the second solution with a mixture of tetrahydrocannabinol and ethanol to obtain a viscous solution or gel, and applying the viscous solution or gel to a transdermal patch or cloth for direct application to human or animal skin.
In the twenty-fifth embodiment of the present invention, a method of manufacturing gel containing a pharmaceutical composition containing tetrahydrocannibinol (xcex949 THC) is provided comprising a first step of mixing carbopol and trolamine in an ethanol:water mixture to form a first viscous solution, a second step of mixing the first viscous solution with a second solution containing ethanol and isopropyl myristate to obtain a third solution, and a third step comprising mixing the third solution with a fourth solution containing xcex949 THC and ethanol to obtain a gel for the direct application to human and/or animal skin.
In the twenty-sixth embodiment of the present invention, a method for manufacturing a pharmaceutical composition comprising a transdermal gel containing extracts of cannabis is provided comprising a first supercritical fluid extraction step wherein 9 THC is extracted from cannabis, a second step comprising dispersing the 9 THC in an ethanol:water mixture, a third step comprising adding trolamine to the ethanol:water mixture to form a first solution, a fourth step comprising mixing the first solution with a second solution containing ethanol and isopropyl myristate to form a third solution, wherein the third solution is a translucent gel for direct application to human skin.